Reduction products of the male sex hormones and of compounds of similar activity and a method of producing the same



Patented Feb. 25, 1941 UNITED STATES PATENT OFFICE DUCIN G THE SAME Walter Schoeller, Berlin, Germany, assignor, by mesne assignments, to Schering Corporation, Bloomfield, N. J., a corporation of New Jersey No Drawing. Application February 23, 1935,

Serial No. 7,830. In Germany February 24,

' 22 Claims.

This invention relates to the production of new compounds of the cyclopentano dimethyl polyhydro phenanthrene series, known also as the etiocholane series (saturated and unsaturated) and including reduction products of the male sex hormones and of compounds of similar physiological activity or chemical constitution, and more particularly to diols of the general formula Ciel-I320: and to diketones of the general formula CmHzaOz and to a method of producing the same.

It has been found that compounds of special physiological activity, or capable of conversion into compounds of high physiological activity, can be produced from the male sexual hormones and from compounds of similar physiological activity having a keto group in their molecule, by reducing said keto group to the corresponding secondary alcohol, group. Whilst, for instance, the male sex hormone of the formula CmHaoOz and the melting point 178 0., possesses an activity of about 150 for the capon unit, the product obtained therefrom by reduction has an efficiency of about 15 for the capon unit. Hence, an increase in. eil'ectiveness of several times the orig- 25 inal value is attainedby this process of -converting the keto group into an alcoholic hydroxy group. Thus, this invention enables the production of highly active preparations of the type of the male sex hormones in a simple and convenient manner.

Said reduction is preferably carried out by first dissolving the product to be reduced in a suitable solvent, such as alcohol,-whereupon the hormones is reduced, for instance, by the addi- 35 tion of metallic sodium, i. e. by means of hydrogen in statu nascendi.

One may also proceed in such a manner, that the solution of the hormone is caused to react with amalgamated aluminum foils in the presence of water, or by allowing catalytically activated hydrogen to act under suitable conditions, such as increased pressure, on the starting material, care being taken that the keto group only is reduced to the alcoholic hydroxy group without, however, complete reduction to the desoxo-product taking place.

As starting material not, only the crystalline male sex hormone of the formula Cl9II3002(I) may be used but also its unsaturated derivatives such as the dehydroandrosterones of the formula C19H2802(II) and the like. It is immaterial from what kind of initial materials these compounds are produced orobtained, whether from animal or vegetable sources or by synthetic means. Thus, the crude extracts of the male sex hormones, as

they are obtained, for instance, from urine, fluids of the human body; organs and the like can be converted by reduction into diols of a substan-' tially higher physiological value.

This invention, furthermore, contemplates also another way of transforming the male seii hormones and the like compounds into diols of higher physiological activity. According to this modification of my process the starting materials are first converted by oxidation into the corresponding diketones of the formula CmHaaOzW) and C1oH2eO2(VI) These diketones are of higher physiological activity than the hydroxy ketones used as starting materials.

The physiological activity of these diketones is still further enhanced if they are converted by reduction into the corresponding dihydroxy compounds of the formula C19H32O2(VII). The latter compounds are the same as those obtained by directly-reducing the starting materials in the manner described above.

The oxidation may be carried out in the usual manner, i. e. with chromic acid at an ordinary temperature, but other oxidation agents may also,

be used, such as copper oxide, mercuric oxide and other similar substances.

Likewise the hydrogenation of the diketone is eifected in the usual manner but consideration must be paid to the fact that there is a possibility of the formation of various isomeric modifications, and that the ratio in which the different isomeric forms are 0 'tained is itself dependent upon the methods of reduction. In accordance with the rule of Aujlers and Skita mainly the trans-modifications re formed by reduction in neutral and alkaline jmedium whilst on the other hand, in acid solution, the cis-modifications are obtained.

The following structural formulas indicate by Way of example the configuration of certain of the compounds used as starting-materials and of those obtained by the processes claimed:

)Iulv so): hormone=androsterone and its isomer, a keto cyclopentano tctradekahydro phenanthrol II and IV I'rnsatul'uted male sex hormone==dehydro androstercne and its isomer, a kuto cyclopontano dodekahydro plienuutlirol Dikctomobtained from II and 1V liihydi'ogl'nuiml male sex lmrnumv ind its isomers The following examples serve to illustrate the invention without, however, limiting the same to them.

Example 1 1 gram of the crystalline male sex hormone of the formula C19H3002 (melting point 178) is dissolved in 250 cc. of alcohol. metallic sodium is added in small portions to /2 gram of the solution. When the metal is dissolved, the

solution is boiled for half an hour, whereupon it is poured into ten times its volume of water, said aqueous solution being then extracted with ether.

The ethereal solution is washed free from alkali,

dried and evaporated.

product intermingled with cryst further purification a crystalline There remains an oily als yielding on colourless compound of the formula C19H32O2(VII).

Example 2 1 gram of a crystalline crude male sex hormone is dissolved in 200 com. of cyclohexanol and after addition hydrogen at 150 C. and a pressure of 35 atmospheres. When the hydrogenatio n is completed,

the reaction solution is freed from the catalyst, evaporated in a vacuum and the residue is extracted with ether. After evaporation of the ether a white crystalline product is obtained which, compared with the starting material, shows at least a five-fold increase in effectiveness.

Example 3 2.41 grams of keto cyclopentano dimethyl tetradekahydro phenanthrol (III) produced as described in U. S. Patent No. 2,184,299, are dissolved in 450 com. of glacial acetic acid. To this solution there is added an amount of chromic acid corresponding to 1.5 atoms of oxygen whereupon it is kept for one day at room temperature. The solvent is then evaporated. From the solution, which is concentrated by evaporation until crystallisation sets in, the diketone is precipitated in crystalline form by the addition of water. On recrystallisation from diluted alcohol a diketone of the formula Ci9H2aOz(V) is obtained in long needles of the melting point 129 C. The yield amounts to about 2 grams or approximately 80-85%. The optical rotation of the product is a: 0.769, MP5": 104.8"

In a manner similar to that described in Example 1, the keto cyclopentano dimethyl dodekahydro phenanthrol, as obtained according to U. S. Patent No. 2,184,299, can be converted by oxidation into the corresponding unsaturated diketone of the formula C19H26O2(VI) which on hydrogenation yields the same hydrogenation product (VII) as is obtained according to Example 1.

Of course, various modifications and changes in the reaction condtions, etc. may be made by those skilled in the art in accordance with the principles set forth herein and in the claims annexed hereto.

What I claim is:

1. A method of improving the physiological action of keto-containing male sex hormones of the general structural formula the dotted line indicating the probable position of the double bond in the unsaturated hormones. comprising subjecting the starting material to the action of agents capable of reducing the kcto group to the secondary alcohol group and of saturating a. double bond when present, whereby compounds of the general formula CwHasOz corresponding to the structural formula CHs H OH

- a any the dotted line indicating the probable position of the double bond in the unsaturated hormones, comprising treating the starting material with an oxidizing agent capable of converting the hydroxy into a keto group, and subjecting the diketone obtained thereby to the action of agents capable of reducing the keto groups to secondary alcohol groups and of saturating the double bond when present, whereby compounds of the general formula Ciel-I320: corresponding to the structural formula CH; on; H] on no W I H are obtained.

5. A method according to claim 4, wherein the selective formation of the various isomeric modifications of the reduction products is effected by carrying out the reduction in alkaline, neutral or acid solution.

6. A method of producing reduction products of keto cyclopentano dimethyl phenanthrols of the general formula ClQHnOB, where a: is 28 or 30 and corresponding to the structural formula iii/V the dotted line indicating the probable position of the double bond in the unsaturated compound, comprising subjecting the starting material to the action of agents capable of reducing the keto group to the secondary alcohol group, said reduction products having the general formula CmHaaO-z and corresponding to the structural formula C Ha

ot/V 7. A method of producing reduction products of keto cyclopentano dimethyl dodekahydro phenanthrols of the general formula CmHzaOz corresponding to the structural formula CH3 CH1 0 MO- M l comprising subjecting the starting material to the action of agents capable of reducing the keto 3 group to the secondary alcohol group and of hydrogenating the double bond in the molecule of said starting material, said reduction products having the general formula 019E320: and corresponding to the structural formula OH H p il 8. A method of producing reduction products of keto cyclopentano dimethyl phenanthrols of the general formula C19HI02 where x is 28 or 30, and corresponding to the structural formula CHa CH3 CH3 0 A MC U the dotted line indicating the probable position of the double bond in the unsaturated compound, comprising subjecting the starting material to the action of an oxidizing agent capable of converting. the hydroxy group into a keto group, and subjecting the diketone obtained therebyto the I action of an agent capable of reducing the keto I groups to secondary alcohol groups and of saturating a double bond when present, said reduc- 4. 1 tion products having the general formula CmI-IszOz and corresponding to the structural formula l (ill n 9. A method of producing reduction products a of keto cyclopentano dimethyl dodecahydro phenanthrols of the genera formula C19H2a0z corresponding to the structural formula cm on, O

. a mm comprising subjecting the starting material to the action of an oxidizing agent capable of converting the hydroxy group into a keto group, and subjecting the diketone obtained thereby to the action of agents capable of reducing the keto groups to secondary alcohol groups, and of hydrogenating the double bond in the molecule of 5 said starting material, said reduction products having the general formula CmHzzOa and corresponding to the structural formula eral formula C19H2BO2 corresponding to the structural formula CH; C ll: 0

I r T\/\/ comprising subjecting keto cyclopentano tetradekahydro phenanthrols of the general formula C19H3o02 corresponding to the structural formula to the action of an oxidizing agent capable of transforming the hydroxy group in said starting material into the keto roup.

11. Diketones of the general formula CmHzaOz and the structural formula 12. A dialcohol of the general formula Ciel-I320: and corresponding to the structural formula CH: H on 13. A method of producing 3,17 dihydroxy cyclopentano dimethyl polyhydro phenanthrene compounds of the general formula 01011320: and corresponding to the structural formula (RHH which comprises hydrogenating a cyclopentano (13,14) dimethyl (10,13) polyhydro phenanthrene compound of the general formula CioHxOz, wherein X is an even number from 26 to 30 inclusive, and at least one of the oxygen atoms is ketonic, to the saturated diol condition, and isolating the hydrogenated compound.

14. In a method of producing 3,17 dihydroxy cyclopentano dimethyl polyhydro phenanthrene compounds of the general formula CmHazOz and corresponding to the structural formula CH3 cm on 11 the step which comprises hydrogenating a diketo (13,17) cyclopentano dimethyl (10,13) polyhydro phenanthrene compound of the general formula CmHzaOz, and recovering the hydrogenated compound.

15. In a method of producing 3,1'7 dihydroxy cyclopentano dimethyl polyhydro phenanthrene compounds of the general formula C19H32Oz and corresponding to the structural formula when n is 28.

17. A method or producing 3,17 dihydroxy cyclopentano dimethyl polyhydro phenanthrene compounds of the general formula C19H32O2 and corresponding to the structural formula CH1 CH3 f on size" which comprises hydrogenating a cyclopentano (13,14) dimethyl (10,13) polyhydro phenanthrene compound of the general formula Ciel-13002, wherein one of the oxygen atoms is ketonic and is in the 17-position, and the other forms part of a hydroxyl group, to the diol condition, and isolating the hydrogenated compound.

18. A method according to claim 4, wherein the selective formation of the various isomeric modifications of the reduction products is efiected v by carrying out the reduction in acid solution.

19 A method according to claim 4, wherein the selective formation of the various isomeric modifications of the reduction products is effected by carrying out the reduction in alkaline solution.

20. A method according to claim 4, wherein the selective formation of the various isomeric modifications of the reduction products is effected by carrying out the reduction in neutral solution.

21. Trans-androstandiol.

22. Cis-andr'ostandiol.

WALTER SCHOELLER. 

